Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.

International audienceSHANK3 (also known as ProSAP2) regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome. Here, we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders. These mutations concern only a small number of individuals, but they shed light on one gene dosage-sensitive synaptic pathway that is involved in autism spectrum disorders

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Advanced glycation end-products (AGEs) and associations with cardio-metabolic, lifestyle and dietary factors in a general population: the NQplus study

Advanced glycation end-products are a heterogeneous group of molecules that are formed during reactions between reducing sugars and proteins. Advanced glycation end-products are thought to play a role in several diseases, including diabetes mellitus and can be measured non-invasively using skin autofluorescence (AF). The aim of this cross-sectional study was to investigate associations between skin AF and cardio-metabolic, lifestyle, and dietary factors within a general population

Advanced glycation end-products (AGEs) and associations with cardio-metabolic, lifestyle, and dietary factors in a general population:The NQplus study

Background: Advanced glycation end-products are a heterogeneous group of molecules that are formed during reactions between reducing sugars and proteins. Advanced glycation end-products are thought to play a role in several diseases, including diabetes mellitus and can be measured non-invasively using skin autofluorescence (AF). The aim of this cross-sectional study was to investigate associations between skin AF and cardio-metabolic, lifestyle, and dietary factors within a general population. Methods: The NQplus study is an ongoing longitudinal study in the surroundings of Wageningen, the Netherlands. In this cross-sectional study, skin AF was measured in 957 participants, aged 20 to 77 years, with the AGE Reader. Logistic regression was used to assess associations between skin AF and the following factors: demographics, adiposity, blood lipids, fasting glucose, HbA(1c), blood pressure, dietary intake, and disease history. Stepwise linear regression was used to identify factors correlating with skin AF. Results: In males, skin AF was significantly associated with age, coffee intake, systolic and diastolic blood pressure, body fat, full fat dairy, and educational level. In females, significant associations were found with age, coffee intake, HbA(1c), diabetes, and eGFR. In the total population, current smoking was positively associated with skin AF. Conclusions: This cross-sectional study in a general population showed that age and coffee intake were associated with skin AF in both males and females. We observed a gender disparity for some of the associations with skin AF, which need to be confirmed by further research. More detailed research is needed to assess the association between skin AF and diet

Side‐effects related to adjuvant CAPOX treatment for colorectal cancer are associated with intermuscular fat area, not with total skeletal muscle or fat, a retrospective observational study

Abstract Aims Chemotherapeutic treatment is regularly accompanied by side‐effects. Hydrophilic chemotherapeutics such as capecitabine and oxaliplatin (CAPOX), often used in colorectal cancer treatment, predominantly accumulate in non‐adipose tissues. Therefore the aim of this paper was to investigate whether body composition and fat infiltration in the muscle (muscle attenuation and intermuscular‐adipose‐tissue [IMAT] content) are associated with chemotherapy‐induced toxicities. Methods In this retrospective observational study, we collected data from 115 colorectal cancer patients receiving adjuvant CAPOX chemotherapy between 2006 and 2015. Information on cancer characteristics were obtained from the Netherlands Cancer Registry. Diagnostic CT scans were retrieved to assess cross‐sectional areas of skeletal muscle and adipose tissue at the third lumbar vertebrae. Information on dose‐limiting toxicity [DLT] and relative administered dose (as % of BSA‐based‐planned‐dose) were retrieved from medical charts. Associations between body composition, muscle quality and chemotherapy‐induced toxicities were determined using Cox‐regression and linear‐regression analyses. Results We found that DLT incidence was 90% in our cohort: 50% had their dose reduced, 30% their next cycle postponed, 4% a full treatment stop and 6% was hospitalized at their first DLT. Most common were reductions in oxaliplatin dose whilst keeping the capecitabine dose constant. Cox regression analysis indicated no association between body composition or muscle quality and DLT during the first treatment cycle or time to the first DLT. Multiple linear regression showed that higher IMAT‐index and IMAT muscle percentage were associated with a lower relative administered dose of oxaliplatin. Conclusions In conclusion; only IMAT, not skeletal or fat area was associated with dose‐limiting toxicities among these CRC patients who received CAPOX treatment

Expression and genetic variability of PCDH11Y, a gene specific to Homo sapiens and candidate for susceptibility to psychiatric disorders.

International audienceSynaptogenesis, the formation of functional synapses, is a crucial step for the development of the central nervous system. Among the genes involved in this process are cell adhesion molecules, such as protocadherins and neuroligins, which are essential factors for the identification of the appropriate partner cell and the formation of synapses. In this work, we studied the expression and the genetic variability of two closely related members of the protocadherin family PCDH11X/Y, located on the X and the Y chromosome, respectively. PCDH11Y is one of the rare genes specific to the hominoid lineage, being absent in other primates. Expression analysis indicated that transcripts of the PCDH11X/Y genes are mainly detected in the cortex of the human brain. Mutation screening of 30 individuals with autism identified two PCDH11Y polymorphic amino acid changes, F885V and K980N. These variations are in complete association, appeared during human evolution approximately 40,000 years ago and represent informative polymorphisms to study Y chromosome variability in populations. We studied the frequency of these variants in males with autism spectrum disorders (n = 110), attention deficit hyperactivity disorder (ADHD; n = 61), bipolar disorder (n = 61), obsessive-compulsive disorder (n = 51), or schizophrenia (n = 61) and observed no significant differences when compared to ethnically-matched control populations. These findings do not support the role of PCDH11Y, or more generally of a frequent specific Y chromosome, in the susceptibility to these neuropsychiatric disorders

Abnormal melatonin synthesis in autism spectrum disorders.

International audienceMelatonin is produced in the dark by the pineal gland and is a key regulator of circadian and seasonal rhythms. A low melatonin level has been reported in individuals with autism spectrum disorders (ASD), but the underlying cause of this deficit was unknown. The ASMT gene, encoding the last enzyme of melatonin synthesis, is located on the pseudo-autosomal region 1 of the sex chromosomes, deleted in several individuals with ASD. In this study, we sequenced all ASMT exons and promoters in individuals with ASD (n=250) and compared the allelic frequencies with controls (n=255). Non-conservative variations of ASMT were identified, including a splicing mutation present in two families with ASD, but not in controls. Two polymorphisms located in the promoter (rs4446909 and rs5989681) were more frequent in ASD compared to controls (P=0.0006) and were associated with a dramatic decrease in ASMT transcripts in blood cell lines (P=2 x 10(-10)). Biochemical analyses performed on blood platelets and/or cultured cells revealed a highly significant decrease in ASMT activity (P=2 x 10(-12)) and melatonin level (P=3 x 10(-11)) in individuals with ASD. These results indicate that a low melatonin level, caused by a primary deficit in ASMT activity, is a risk factor for ASD. They also support ASMT as a susceptibility gene for ASD and highlight the crucial role of melatonin in human cognition and behavior.Molecular Psychiatry (2008) 13, 90-98; doi:10.1038/sj.mp.4002016; published online 15 May 2007

Study protocol of a randomized controlled trial evaluating home treatment with peer support for acute mental health crises (HoPe)

Background: Home treatment (HT) is a treatment modality for patients with severe mental illness (SMI) in acute mental crises. It is frequently considered equivalent to psychiatric inpatient treatment in terms of treatment outcome. Peer Support (PS) means that people with lived experience of a mental illness are trained to support others on their way towards recovery. While PS is growing in international importance and despite a growing number of studies supporting its benefits, it is still not comprehensively implemented into routine care. The HoPe (Home Treatment with Peer Support) study investigates a combination of both - HT and PS - to provide further evidence for a recovery-oriented treatment of psychiatric patients. Methods: In our randomized controlled trial (RCT), HT with PS is compared with HT without PS within a network of eight psychiatric clinical centers from the North, South and East of Germany. We investigate the effects of a combination of both approaches with respect to the prevention of relapse/recurrence defined as first hospitalization after randomization (primary outcome), disease severity, general functioning, self-efficacy, psychosocial health, stigma resistance, recovery support, and service satisfaction (secondary outcomes). A sample of 286 patients will be assessed at baseline after admission to HT care (data point t(0)) and randomized into the intervention (HT+ PS) and control arm (HT). Follow-Up assessments will be conducted 2, 6 and 12 months after admission (resulting in three further data points, t(1) to t(3)) and will be analyzed via intention-to-treat approach. Discussion: This study may determine the positive effects of PS added to HT, prove additional evidence for the efficacy of PS and thereby facilitate its further implementation into psychiatric settings. The aim is to improve quality of mental health care and patients' recovery as well as to reduce the risk of relapses and hospitalizations for patients with SMI